Henke Guido, Lindner Lars H, Vogeser Michael, Eibl Hans-Jörg, Wörner Jürgen, Müller Arndt C, Bamberg Michael, Wachholz Kirsten, Belka Claus, Jendrossek Verena
Department of Radiooncology, University Hospital Tübingen, Hoppe-Seyler-Str 3, 72076 Tübingen, Germany.
Radiat Oncol. 2009 Oct 23;4:46. doi: 10.1186/1748-717X-4-46.
Alkylphosphocholines represent promising antineoplastic drugs that induce cell death in tumor cells by primary interaction with the cell membrane. Recently we could show that a combination of radiotherapy with Erufosine, a paradigmatic intravenously applicable alkylphosphocholine, in vitro leads to a clear increase of irradiation-induced cell death. In view of a possible combination of Erufosine and radiotherapy in vivo we determined the pharmacokinetics and bioavailability as well as the tolerability of Erufosine in nude mice.
NMRI (nu/nu) nude mice were treated by intraperitoneal or subcutaneous injections of 5 to 40 mg/kg body weight Erufosine every 48 h for one to three weeks. Erufosine-concentrations were measured in brain, lungs, liver, small intestine, colon, spleen, kidney, stomach, adipoid tissue, and muscle by tandem-mass spectroscopy. Weight course, blood cell count and clinical chemistry were analyzed to evaluate general toxicity.
Intraperitoneal injections were generally well tolerated in all dose groups but led to a transient loss of the bodyweight (<10%) in a dose dependent manner. Subcutaneous injections of high-dose Erufosine caused local reactions at the injection site. Therefore, this regimen at 40 mg/kg body weight Erufosine was stopped after 14 days. No gross changes were observed in organ weight, clinical chemistry and white blood cell count in treated compared to untreated controls except for a moderate increase in lactate dehydrogenase and aspartate-aminotransferase after intensive treatment. Repeated Erufosine injections resulted in drug-accumulation in different organs with maximum concentrations of about 1000 nmol/g in spleen, kidney and lungs.
Erufosine was well tolerated and organ-concentrations surpassed the cytotoxic drug concentrations in vitro. Our investigations establish the basis for a future efficacy testing of Erufosine in xenograft tumor models in nude mice alone and in combination with chemo- or radiotherapy.
烷基磷胆碱是一类很有前景的抗肿瘤药物，可通过与细胞膜的直接相互作用诱导肿瘤细胞死亡。最近我们发现，放疗与依鲁福辛（一种典型的静脉注射用烷基磷胆碱）联合应用在体外可显著增加辐射诱导的细胞死亡。鉴于依鲁福辛与放疗在体内联合应用的可能性，我们测定了依鲁福辛在裸鼠体内的药代动力学、生物利用度及耐受性。
将NMRI（nu/nu）裸鼠每48小时腹腔或皮下注射5至40mg/kg体重的依鲁福辛，持续1至3周。采用串联质谱法测定脑、肺、肝、小肠、结肠、脾、肾、胃、脂肪组织和肌肉中的依鲁福辛浓度。分析体重变化过程、血细胞计数和临床化学指标以评估总体毒性。
所有剂量组的腹腔注射一般耐受性良好，但会导致体重短暂下降（<10%），且呈剂量依赖性。皮下注射高剂量依鲁福辛会引起注射部位局部反应。因此，在14天后停止了40mg/kg体重依鲁福辛的该给药方案。与未治疗的对照组相比，治疗组的器官重量、临床化学指标和白细胞计数未观察到明显变化，但在强化治疗后乳酸脱氢酶和天冬氨酸转氨酶有中度升高。重复注射依鲁福辛导致不同器官出现药物蓄积，脾脏、肾脏和肺中的最大浓度约为1000nmol/g。
依鲁福辛耐受性良好，器官浓度超过了体外细胞毒性药物浓度。我们的研究为未来在裸鼠异种移植肿瘤模型中单独及联合化疗或放疗对依鲁福辛进行疗效测试奠定了基础。
